Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease

TY - JOUR

T1 - Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease

AU - Zeiser, Robert

AU - Polverelli, Nicola

AU - Ram, Ron

AU - Hashmi, Shahrukh K

AU - Chakraverty, Ronjon

AU - Middeke, Jan Moritz

AU - Musso, Maurizio

AU - Giebel, Sebastian

AU - Uzay, Ant

AU - Langmuir, Peter

AU - Hollaender, Norbert

AU - Gowda, Maanasa

AU - Stefanelli, Tommaso

AU - Lee, Stephanie J

AU - Teshima, Takanori

AU - Locatelli, Franco

AU - REACH3 Investigators

N1 - Copyright © 2021 Massachusetts Medical Society.

PY - 2021/7/15

Y1 - 2021/7/15

N2 - BACKGROUND: Chronic graft-versus-host disease (GVHD), a major complication of allogeneic stem-cell transplantation, becomes glucocorticoid-refractory or glucocorticoid-dependent in approximately 50% of patients. Robust data from phase 3 randomized studies evaluating second-line therapy for chronic GVHD are lacking. In retrospective surveys, ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory or -dependent chronic GVHD.METHODS: This phase 3 open-label, randomized trial evaluated the efficacy and safety of ruxolitinib at a dose of 10 mg twice daily, as compared with the investigator's choice of therapy from a list of 10 commonly used options considered best available care (control), in patients 12 years of age or older with moderate or severe glucocorticoid-refractory or -dependent chronic GVHD. The primary end point was overall response (complete or partial response) at week 24; key secondary end points were failure-free survival and improved score on the modified Lee Symptom Scale at week 24.RESULTS: A total of 329 patients underwent randomization; 165 patients were assigned to receive ruxolitinib and 164 patients to receive control therapy. Overall response at week 24 was greater in the ruxolitinib group than in the control group (49.7% vs. 25.6%; odds ratio, 2.99; P<0.001). Ruxolitinib led to longer median failure-free survival than control (>18.6 months vs. 5.7 months; hazard ratio, 0.37; P<0.001) and higher symptom response (24.2% vs. 11.0%; odds ratio, 2.62; P = 0.001). The most common (occurring in ≥10% patients) adverse events of grade 3 or higher up to week 24 were thrombocytopenia (15.2% in the ruxolitinib group and 10.1% in the control group) and anemia (12.7% and 7.6%, respectively). The incidence of cytomegalovirus infections and reactivations was similar in the two groups.CONCLUSIONS: Among patients with glucocorticoid-refractory or -dependent chronic GVHD, ruxolitinib led to significantly greater overall response, failure-free survival, and symptom response. The incidence of thrombocytopenia and anemia was greater with ruxolitinib. (Funded by Novartis and Incyte; REACH3 ClinicalTrials.gov number, NCT03112603.).

AB - BACKGROUND: Chronic graft-versus-host disease (GVHD), a major complication of allogeneic stem-cell transplantation, becomes glucocorticoid-refractory or glucocorticoid-dependent in approximately 50% of patients. Robust data from phase 3 randomized studies evaluating second-line therapy for chronic GVHD are lacking. In retrospective surveys, ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory or -dependent chronic GVHD.METHODS: This phase 3 open-label, randomized trial evaluated the efficacy and safety of ruxolitinib at a dose of 10 mg twice daily, as compared with the investigator's choice of therapy from a list of 10 commonly used options considered best available care (control), in patients 12 years of age or older with moderate or severe glucocorticoid-refractory or -dependent chronic GVHD. The primary end point was overall response (complete or partial response) at week 24; key secondary end points were failure-free survival and improved score on the modified Lee Symptom Scale at week 24.RESULTS: A total of 329 patients underwent randomization; 165 patients were assigned to receive ruxolitinib and 164 patients to receive control therapy. Overall response at week 24 was greater in the ruxolitinib group than in the control group (49.7% vs. 25.6%; odds ratio, 2.99; P<0.001). Ruxolitinib led to longer median failure-free survival than control (>18.6 months vs. 5.7 months; hazard ratio, 0.37; P<0.001) and higher symptom response (24.2% vs. 11.0%; odds ratio, 2.62; P = 0.001). The most common (occurring in ≥10% patients) adverse events of grade 3 or higher up to week 24 were thrombocytopenia (15.2% in the ruxolitinib group and 10.1% in the control group) and anemia (12.7% and 7.6%, respectively). The incidence of cytomegalovirus infections and reactivations was similar in the two groups.CONCLUSIONS: Among patients with glucocorticoid-refractory or -dependent chronic GVHD, ruxolitinib led to significantly greater overall response, failure-free survival, and symptom response. The incidence of thrombocytopenia and anemia was greater with ruxolitinib. (Funded by Novartis and Incyte; REACH3 ClinicalTrials.gov number, NCT03112603.).

KW - Adolescent

KW - Adult

KW - Aged

KW - Child

KW - Cytomegalovirus Infections/etiology

KW - Female

KW - Glucocorticoids/therapeutic use

KW - Graft vs Host Disease/drug therapy

KW - Humans

KW - Immunologic Factors/adverse effects

KW - Janus Kinases/antagonists & inhibitors

KW - Male

KW - Middle Aged

KW - Nitriles

KW - Photopheresis

KW - Pyrazoles/adverse effects

KW - Pyrimidines

KW - Survival Analysis

KW - Thrombocytopenia/chemically induced

KW - Treatment Failure

KW - Young Adult

U2 - 10.1056/NEJMoa2033122

DO - 10.1056/NEJMoa2033122

M3 - SCORING: Journal article

C2 - 34260836

VL - 385

SP - 228

EP - 238

JO - NEW ENGL J MED

JF - NEW ENGL J MED

SN - 0028-4793

IS - 3

ER -